Dementia and the Prevalence of Alzheimer's Disease
Dementia is a neurodegenerative disorder that affects as many as 10% of individuals over 65 years of age, and more than 35% of those over 85 (Hofman et al. Int. J. Epidemiol. 1991;20:736-748; Jorm and Jolley. Neurology 1998;1:728-733; Lobo et al. Neurology 2000;4Suppl5:S4-S9). Dementia is a complex syndrome and is typically progressive or chronic. The spectrum of this disorder is broad-sweeping and encompasses multiple cognitive functions, including learning, memory, thinking, calculation, language, judgment, comprehension, and spatial and temporal recognition. In addition, the syndrome can be preceded or accompanied by disruption in emotional states, including emotional control, social behavior, and motivation.
Of the diseases leading to dementia, Alzheimer's Disease (AD) is the most common, accounting for greater than half the cases in people over 65 years of age. First recognized nearly a century ago (Alzheimer. Algemeine Zeitschrift fur Pschiatrie. 1907;64:146-148). Alzheimer's disease (AD) is a devastating disorder, affecting nearly 2-3 million individuals in the United States and about 15 million people world-wide (including all races and ethnic groups). Moreover, because advanced age in the biggest risk factor for AD, the prevalence of this disorder doubles every 5 years beyond age 65 (National Institute on Aging: Prevalence and costs of Alzheimer's disease. Progress Report on Alzheimer's Disease. NIH Publication No. 99,3616, November 1998; Polyikoski et al. Neurology 2001;56:1690-1696).
Pathology of Alzheimer's Disease
The pathological hallmarks of clinical AD are confined to the central nervous system (CNS) and comprise two principal features: amyloid deposits and neurofibrillary tangles (NFT). Amyloidosis—the deposition of amyloid—occurs through the vascular and neuronal architecture of the CNS.
Although amyloidosis occurs to a limited extent in probably all individuals, especially with advanced age, it is aberrantly high in AD and related disorders. The main molecular component of amyloid is β-amyloid, a highly hydrophobic peptide, derived from processing of the amyloid precursor protein (APP; See FIG. 6). This peptide aggregates into filaments in an anti-β-pleated sheet structure. Elevated expression disrupts the structure and function of neuronal and glial cells, ultimately resulting in extensive cell death in regions of the brain underlying higher cognitive functions, (Francis et al. J. Neurol. Neurosurg. Psychiatry 1999;66:137-147).
These pathological hallmarks, however, reflect terminal points of a lengthy disease process. Consequently, post-mortem brain studies have yielded little insight into the molecular and biochemical components involved in the initiation and progression of this disease. Underscoring this issue is the molecular complexity of amyloid, which comprises many additional proteins, including α1′-anti-chymotrypsin (Abraham et al. Cell 52:487-501, 1988), cathepsin D (Cataldo et al. Brain Res. 1990;513:181-192) and apolipoprotein E (apoE) (Namba et al. Brain Res. 1991;541:163-166; Wisniewski and Frangione. Neurosci. Lett. 1992;135:235-238; Strittmatter et al. Proc. Nat. Acad. Sci. USA 1993;90:1977-1981).
Etiology of Alzheimer's Disease
Although amyloidosis is a conserved feature of AD, the underlying etiology is highly complex and the vast majority of instances likely involves multiple genetic and environmental determinants. AD has been divided into two categories: Familial AD (FAD) and Sporadic AD. FAD is associated with mutations in least three known loci: presenilin 1 (PS1), presenilin 2 (PS2) and amyloid precursor protein (APP) genes. Studies of FAD have underscored the importance of amyloid β-peptide (Aβ) in AD, but are limited in scope: FAD only accounts for a small fraction of AD cases (less than 5%), has a much earlier age onset (often in the 40's) and follows clear patterns of inheritance (Bird et al. Ann. Neurol. 1989;25:12-25; Heston and White. Behavior Genet. 1978;8:315-331; Pericak-Vance et al. Exp. Neurol. 1988; 102:271-279).
In contrast Sporadic AD can reflect a genetic etiology, but it is not a tight linkage. The ε4 allele of the apoliprotein E locus, for example, increases the risk of developing AD; however, its presence does not guarantee AD, nor does its absence preclude it. (Consensus report of the Working Group. Neurobiology of Aging 1998;19:109-116).
The vast majority of AD cases, therefore, will likely comprise a complex etiology, implicating multiple genetic and environmental factors. In light of such constraints, many investigations have focused on identifying biological markers that correlate with different stages of AD. Candidates for such markers have included cerebrospinal fluid profiles, peripheral tissue markers, pharmacologic and neuroendocrine probes, and behavioral and biochemical correlates. (See, e.g., Neurobiology of Aging 1998;19:109-116 for a review).
Nevertheless, such biological markers are not likely to provide a cure-all for at least two reasons. First, the extended time course of AD poses the inescapable challenge of separating normal changes during aging, such as impairments of cognitive abilities, from pathogenic ones. Second, dietary, environmental, and genetic factors are not easily controlled with this approach, presenting the additional challenge of resolving diagnostic effects within a heterogeneous background. At present, AD remains incurable. Nor is there available a treatment that effectively prevents AD or reverses its symptoms.
Thus, there is a need in the art to develop new approaches to identify candidate compounds effective to inhibit and treat symptoms or clinical manifestations of AD and related disorders. The present invention meets this need by disclosing new mechanistic and temporal links between the induction of an insulin-resistant Type 2 diabetes state—a known risk factor for AD—and the subsequent appearance of cognitive defects and β-amyloid pathologies in the brain. In turn, these findings reveal specific and unexpected uses for D-pinitol—an insulin sensitizing compound—that include inhibiting AD pathology.